Biophysical Society Thematic Meeting| Lima 2019

Revisiting the Central Dogma of Molecular Biology at the Single-Molecule Level

Poster Abstracts

45-POS Board 45 COARSE-GRAINED COMPUTATIONAL SIMULATION OF PHOSPHOLIPID AGGREGATES IN THE PRESENCE OF ANTIMICROBIAL PEPTIDE LL-37

Yeny Y Pillco Valencia 1 ; Gabriel A Da Hora 1 ; Thereza A Soares 1 ; 1 universidade Federal De Pernambuco, Quimica, Recife, Brazil

Antimicrobial peptides (AMPs) are part of the innate immune response found in all living organisms, they have a broad spectrum activity against bacteria, viruses and fungi. This biological compounds in contact with the target microbial membrane can cause cell rupture through several hypothetical mechanisms: barrel, aggregate, carpet and toroidal pore model. The first amphiphilic peptide isolated from human cells is LL-37 and belongs to the cathelicidin family. The AMP LL-37 (LLGDF-FRKSK-EKIGK-EFKRI-VQRIK-DFLRN-LVPRT-ES) has a charge of +6 and an amphipathic alpha-helical structure at physiological pH. Despite several studies, the molecular mechanism of action of LL-37 is still not fully understood, therefore our objective is to investigate the possible mechanism of molecular action of this LL-37 in phospholipid membranes. Experimental measures such as Small-angle X-ray scattering (SAXS) and electronic microscopy suggest that LL-37 destabilizes 1-palmitoyl-2-oleoyl-sn-glycero-3- phosphoglycerol (POPG) bilayers and induces the disappearance of multilamellar bilayers and the appearance of micelles in a concentration-dependent manner. We have performed atomistic and coarse-grained MD simulations to bring higher resolution structural information into the experimental picture. We have performed simulations of POPG and POPC bilayer at different concentrations of the peptide to investigate the process of LL-37 induced transition of phospholipidic bilayers. Our simulations show that LL-37 binds to POPG bilayer in a horizontal orientation. At low peptide concentrations of 15:1 (ratio on mass lipid: peptide), LL-37 remains at the headgroup area throughout 3 μs, but above a concentration of 9:1 we observe a slow migration of the peptide to the hydrophobic region of the bilayer. Interestingly, the process appears to take place faster at the atomistic than at the coarse-grained levels, but further sampling is required to verify this claim. We argue that the POPG bilayer is destabilized by LL-37 via a carpet-like mechanism consistent with experimental structural data.

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